Association of imaging biomarkers and local activation of complement in aqueous humor of patients with early forms of age-related macular degeneration

Abstract Purpose To investigate a possible correlation between established imaging biomarkers for age-related macular degeneration and local complement system activation, measured in aqueous humor (AH) of patients with early stages of age-related macular degeneration (AMD) and controls. Methods This analysis included prospectively acquired AH samples of 106 eyes (35 with early/intermediate AMD, 71 controls). The levels of complement protein 3 (C3), 4 (C4), 5 (C5); activation products of complement factor 3a (C3a) and Ba, C3b/iC3b; complement factors B, D, H, I (CFB, CFD, CFH, CFI); and total protein concentration were analyzed. Quantitative levels of complement factors were correlated to the presence of reticular pseudodrusen (RPD), the presence of hyperreflective foci (HRF), and total drusen volume (DV) graded on imaging by spectral-domain optical coherence tomography and using Spearman’s rank correlation test. Results DV correlated with C3b/iC3b (r = 0.285; P = 0.034), C3a (r = 0.200; P = 0.047), Ba (r = 0.262; P = 0.009), and C5 (r = 430; P = 0.005), and showed a tendency towards correlation with C3a (r = 0.198; P = 0.057). HRF correlated significantly with C5 (r = 0.388; P = 0.011) and RPD showed a tendency towards correlation with CFB (r = 0.196; P = 0.050). Conclusion In patients with early AMD, HRF and drusen parameters but not RPD show low to fair levels of correlation with local complement activation in patients’ AH. Better understanding of complement activation could provide some insights into the pathogenesis of AMD. Imaging biomarkers could be useful to identify suitable patients for future clinical trials with complement-modulating therapies.

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A Review of Completed and Ongoing Complement Inhibitor Trials for Geographic Atrophy Secondary to Age-Related Macular Degeneration

Journal of Clinical Medicine ◽

10.3390/jcm10122580 ◽

2021 ◽

Vol 10 (12) ◽

pp. 2580

Author(s):

Omar A. Halawa ◽

Jonathan B. Lin ◽

Joan W. Miller ◽

Demetrios G. Vavvas

Keyword(s):

Macular Degeneration ◽

Geographic Atrophy ◽

Age Related Macular Degeneration ◽

Western World ◽

Complement Factor ◽

Complement Protein ◽

Pivotal Phase ◽

Complement Inhibition ◽

Exudative Amd ◽

Age Related

Age-related macular degeneration (AMD) is a leading cause of irreversible blindness among older adults in the Western world. While therapies exist for patients with exudative AMD, there are currently no approved therapies for non-exudative AMD and its advanced form of geographic atrophy (GA). The discovery of genetic variants in complement protein loci with increased susceptibility to AMD has led to the investigation of the role of complement inhibition in AMD with a focus on GA. Here, we review completed and ongoing clinical trials evaluating the safety and efficacy of these studies. Overall, complement inhibition in GA has yielded mixed results. The inhibition of complement factor D has failed pivotal phase 3 trials. Studies of C3 and C5 inhibition meeting their primary endpoint are limited by high rates of discontinuation and withdrawal in the treatment arm and higher risks of conversion to exudative AMD. Studies evaluating other complement members (CFB, CFH, CFI and inhibitors of membrane attack complex—CD59) are ongoing and could offer other viable strategies.

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Local complement activation in aqueous humor in patients with age-related macular degeneration

Molecular Immunology ◽

10.1016/j.molimm.2017.06.133 ◽

2017 ◽

Vol 89 ◽

pp. 163 ◽

Cited By ~ 1

Author(s):

Michael Kirschfink ◽

Tina Schick ◽

Marlin Steinhauer ◽

Alexander Aslanidis ◽

Lebriz Altay ◽

...

Keyword(s):

Macular Degeneration ◽

Aqueous Humor ◽

Complement Activation ◽

Age Related Macular Degeneration ◽

Age Related

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Complement factors and reticular pseudodrusen in intermediate age-related macular degeneration staged by multimodal imaging

BMJ Open Ophthalmology ◽

10.1136/bmjophth-2019-000361 ◽

2020 ◽

Vol 5 (1) ◽

pp. e000361 ◽

Cited By ~ 1

Author(s):

Anne M Lynch ◽

Alan G Palestine ◽

Brandie D Wagner ◽

Jennifer L Patnaik ◽

Ashley A Frazier-Abel ◽

...

Keyword(s):

Macular Degeneration ◽

Factor H ◽

Age Related Macular Degeneration ◽

Complement Factor ◽

Factor B ◽

Complement Factors ◽

Factor I ◽

Reticular Pseudodrusen ◽

Age Related ◽

Complement Dysregulation

ObjectiveSystemic activation of the complement system in intermediate age-related macular degeneration (AMD) is understudied. Moreover, links between the presence of reticular pseudodrusen (RPD) and systemic complement dysregulation have not been studied. The aim of this study was to determine if there is a difference in plasma complement factor levels in intermediate AMD compared with controls, and if complement levels are related to the presence of RPD.Methods and analysisLevels of complement factors C1q (µg/mL), C4 (µg/mL), C2 (µg/mL), Mannose Binding Lectin (ng/mL), C4b (µg/mL), C3 (µg/mL), factor B (µg/mL), factor D (µg/mL), properdin (µg/mL), C3a (ng/mL), iC3b/C3b (ng/mL), Ba (ng/mL), factor H (µg/mL), factor I (µg/mL), C5 (µg/mL), C5a (pg/mL) and SC5b-9 (ng/mL) were measured in plasma.Results109 cases and 65 controls were included in the study. Thirty-nine (36%) cases had RPD. Significantly lower systemic levels of: C1q (OR 0.96, 95% CI 0.94 to 0.98), factor B (OR 0.98, 95% CI 0.96 to 0.99), iC3b/C3b (OR 0.97, 95% CI 0.95 to 0.98), factor H (OR 0.99, 95% CI 0.98 to 0.99), factor I (OR 0.83, 95% CI 0.77 to 0.89) and C5 (OR 0.94, 95% CI 0.90 to 0.98) were found in cases versus controls. Significantly elevated levels of: C2 (OR 1.29, 95% CI 1.07 to 1.59), C3a (OR 1.03, 95% CI 1.01 to 1.05) Ba (OR 1.03, 95% CI 1.01 to 1.05) and C5a (OR 1.04, 95% CI 1.02 to 1.07) were found in cases versus controls. Systemic levels of complement factors measured were not related to the presence of RPD.ConclusionsLevels of several systemic complement pathway factors were found to be altered in intermediate AMD. Systemic levels of complement factors were not related to RPD.

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Local complement activation in aqueous humor in patients with age-related macular degeneration

Eye ◽

10.1038/eye.2016.328 ◽

2017 ◽

Vol 31 (5) ◽

pp. 810-813 ◽

Cited By ~ 29

Author(s):

T Schick ◽

M Steinhauer ◽

A Aslanidis ◽

L Altay ◽

M Karlstetter ◽

...

Keyword(s):

Macular Degeneration ◽

Aqueous Humor ◽

Complement Activation ◽

Age Related Macular Degeneration ◽

Age Related

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Control of Complement Activation by the Long Pentraxin PTX3: Implications in Age-Related Macular Degeneration

Frontiers in Pharmacology ◽

10.3389/fphar.2020.591908 ◽

2020 ◽

Vol 11 ◽

Author(s):

Matteo Stravalaci ◽

Francesca Davi ◽

Raffaella Parente ◽

Marco Gobbi ◽

Barbara Bottazzi ◽

...

Keyword(s):

Macular Degeneration ◽

Complement Activation ◽

Hot Spot ◽

Alternative Pathway ◽

Retinal Pigment ◽

Factor H ◽

Age Related Macular Degeneration ◽

Complement Factor ◽

Rpe Cells ◽

Age Related

Dysregulation of the complement system is central to age-related macular degeneration (AMD), the leading cause of blindness in the developed world. Most of the genetic variation associated with AMD resides in complement genes, with the greatest risk associated with polymorphisms in the complement factor H (CFH) gene; factor H (FH) is the major inhibitor of the alternative pathway (AP) of complement that specifically targets C3b and the AP C3 convertase. Long pentraxin 3 (PTX3) is a soluble pattern recognition molecule that has been proposed to inhibit AP activation via recruitment of FH. Although present in the human retina, if and how PTX3 plays a role in AMD is still unclear. In this work we demonstrated the presence of PTX3 in the human vitreous and studied the PTX3-FH-C3b crosstalk and its effects on complement activation in a model of retinal pigment epithelium (RPE). RPE cells cultured in inflammatory AMD-like conditions overexpressed the PTX3 protein, and up-regulated AP activating genes. PTX3 bound RPE cells in a physiological setting, however this interaction was reduced in inflammatory conditions, whereby PTX3 had no complement-inhibiting activity on inflamed RPE. However, on non-cellular surfaces, PTX3 formed a stable ternary complex with FH and C3b that acted as a “hot spot” for complement inhibition. Our findings suggest a protective role for PTX3 in response to complement dysregulation in AMD and point to a novel mechanism of complement regulation by this pentraxin with potential implications in pathology and pharmacology of AMD.

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